Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 30
Filter
Add more filters










Publication year range
1.
ACS Med Chem Lett ; 7(5): 482-6, 2016 May 12.
Article in English | MEDLINE | ID: mdl-27190597

ABSTRACT

[(18)F]FECUMI-101 ([(18)F]1) is a 5HT1AR ligand demonstrating specific binding in brain regions corresponding to the distribution of 5-HT1AR in baboons. However, we detected moderate uptake of [(18)F]1 in baboon thalamus, a brain region lacking 5-HT1AR. We sought to investigate the relative binding of [(18)F]1 to 5-HT1AR, α1R, and 5-HT7R in vitro. Using autoradiography in human brain sections, specific binding of [(18)F]1 to 5-HT1AR was confirmed. However, [(18)F]1 also showed 26% binding to α1R in PFC. The hippocampal formation exhibited 51% and 92% binding of [(18)F]1 to α1R and 5-HT1AR, respectively. Thalamus and cerebellum showed very little binding. There is no measurable specific binding of [(18)F]1 to 5-HT7R and no effect of temperature on [(18)F]1 specific binding to 5-HT1AR or α1R. These results indicate that, while [(18)F]FECUMI-101 is not a completely selective 5-HT1AR ligand for receptor quantification, it may be useful for occupancy measurements of drugs acting at 5-HT1AR in vivo.

2.
J Labelled Comp Radiopharm ; 57(13): 705-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25359578

ABSTRACT

Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation, and recent evidence suggests that an altered mTOR signaling pathway plays a central role in the pathogenesis of aging, tumor progression, neuropsychiatric, and major depressive disorder. Availability of a mTOR-specific PET tracer will facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. Towards this we have developed the radiosynthesis of [(18)F]1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-(2-fluoroethyl)urea [(18)F]ATPFU ([(18)F]1) as an mTOR PET ligand. Synthesis of reference 1 and the precursor for radiolabeling, 4-(4-8-oxa-3-azabicyclo[3.2.1]-octan-3yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6yl)aniline (10), were achieved from beta-chloroaldehyde 3 in 4 and 5 steps, respectively, with an overall yield of 25-28%. [(18)F]Fluoroethylamine was prepared by heating N-[2-(toluene-4-sulfonyloxy)ethyl]phthalimide with [(18)F]fluoride ion in acetonitrile. [(18)F]1 was obtained by slow distillation under argon of [(18) F]FCH2CH2NH2 into amine 10 that was pre-treated with triphosgene at 0-5 °C. The total time required for the two-step radiosynthesis including semi-preparative HPLC purification was 90 min, and the overall radiochemical yield of [(18)F]1 for the process was 15 ± 5% based on [(18)F]fluoride ion (decay corrected). At the end of synthesis (EOS), the specific activity was 37-74 GBq/µmol (N = 6).


Subject(s)
Adenine/analogs & derivatives , Fluorine Radioisotopes/chemistry , Phenylurea Compounds/chemical synthesis , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adenine/chemical synthesis , Adenine/pharmacology , Ligands , Phenylurea Compounds/pharmacology , Radiopharmaceuticals/pharmacology
3.
Bioorg Med Chem Lett ; 24(19): 4759-4762, 2014 Oct 01.
Article in English | MEDLINE | ID: mdl-25182564

ABSTRACT

5-HT1AR agonist or partial agonists are established drug candidates for psychiatric and neurological disorders. We have reported the synthesis and evaluation of a series of high affinity 5-HT1AR partial agonist PET imaging agents with greater selectivity over α-1AR. The characteristic of these molecules are 3,5-dioxo-(2H,4H)-1,2,4-triazine skeleton tethered to an arylpiperazine unit through an alkyl side chain. The most potent 5-HT1AR agonistic properties were found to be associated with the molecules bearing C-4 alkyl group as the linker. Therefore development of 3,5-dioxo-(2H,4H)-1,2,4-triazine bearing arylpiperazine derivatives may provide high affinity selective 5-HT1AR ligands. Herein we describe the synthesis and evaluation of the binding properties of a series of arylpiperazine analogues of 3,5-dioxo-(2H,4H)-1,2,4-triazine.


Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Triazines/pharmacology , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Structure , Piperazines/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemistry , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistry
4.
Bioorg Med Chem ; 21(17): 5598-604, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23816046

ABSTRACT

The 5-HT1AR partial agonist PET radiotracer, [(11)C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki=0.1nM; Emax=77%; EC50=0.65nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [(18)F]fluoroethyltosylate in DMSO in the presence of 1.6equiv of K2CO3 in 45±5% yield (EOS). PET shows [(18)F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [(18)F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [(18)F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET.


Subject(s)
Piperazines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Triazines/chemical synthesis , Animals , Blood-Brain Barrier/metabolism , Brain/diagnostic imaging , Fluorine Radioisotopes/chemistry , Papio , Piperazines/chemistry , Positron-Emission Tomography , Protein Binding , Radiopharmaceuticals/chemistry , Receptor, Serotonin, 5-HT1A/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/chemistry , Triazines/chemistry
5.
Bioorg Med Chem Lett ; 23(14): 4191-4, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23743281

ABSTRACT

Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170°C at high radiochemical purity and specific activity (1-2Ci/µmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R.


Subject(s)
Pyrazoles/chemistry , Radiopharmaceuticals/chemical synthesis , Receptor, IGF Type 1/antagonists & inhibitors , Triazines/chemistry , Fluorine Radioisotopes/chemistry , Humans , Ligands , Neoplasm Grading , Neoplasms/diagnostic imaging , Positron-Emission Tomography , Protein Binding , Pyrazoles/chemical synthesis , Radiography , Radiopharmaceuticals/metabolism , Receptor, IGF Type 1/metabolism , Triazines/chemical synthesis
6.
Brain Res ; 1507: 11-8, 2013 Apr 24.
Article in English | MEDLINE | ID: mdl-23454434

ABSTRACT

[11C]CUMI-101 is the first selective serotonin receptor (5-HT1AR) partial agonist radiotracer for positron emission tomography (PET) tested in vivo in nonhuman primates and humans. We evaluated specific binding of [3H]CUMI-101 by quantitative autoradiography studies in postmortem baboon and human brain sections using the 5-HT1AR antagonist WAY-100635 as a displacer. The regional and laminar distributions of [3H]CUMI-101 binding in baboon and human brain sections matched the known distribution of [3H]8-OH-DPAT and [3H]WAY-100635. Prazosin did not measurably displace [3H]CUMI-101 binding in baboon or human brain sections, thereby ruling out [3H]CUMI-101 binding to α1-adrenergic receptors. This study demonstrates that [11C]CUMI-101 is a selective 5-HT1AR ligand for in vivo and in vitro studies in baboon and human brain.


Subject(s)
Brain/metabolism , Piperazines/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/metabolism , Triazines/metabolism , Animals , Autoradiography , Brain/anatomy & histology , Brain/diagnostic imaging , Drug Partial Agonism , Humans , Ligands , Papio , Positron-Emission Tomography , Tritium
7.
Drug Discov Today ; 18(3-4): 173-84, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23092894

ABSTRACT

Radioligands for PET imaging of glutamate receptors will have the potential for studying neurological and neuropsychiatric disorders and their diagnosis and therapeutic intervention. Glutamate is the major excitatory neurotransmitter in the brain and is implicated in the pathophysiology of many neurodegenerative and neuropsychiatric disorders. Glutamate and its receptors are potential targets in the treatment of these disorders. Glutamate signaling is mediated through ionotropic and metabotropic receptors. The abundant concentration of these receptors can facilitate their in vivo quantification using positron emission tomography (PET). Glutamate receptors are a potentially important set of targets for monitoring disease progression, for evaluating the effect of therapy and for new treatment development based on the quantification of receptor occupancy. Here, we review the PET and single-photon emission computed tomography (SPECT) radioligands that have been developed for imaging glutamate receptors in living brain.


Subject(s)
Brain/diagnostic imaging , Radioactive Tracers , Receptors, Glutamate/metabolism , Animals , Brain/metabolism , Humans , Positron-Emission Tomography , Tomography, Emission-Computed, Single-Photon
8.
J Pharmacol Sci ; 120(3): 254-7, 2012.
Article in English | MEDLINE | ID: mdl-23076129

ABSTRACT

Serotonin (5-HT) 1A receptors exist in high and low affinity states. Agonist ligands bind preferentially to the high affinity state receptors, providing a more functionally relevant measure than antagonist binding. We now report comparison of 5-HT(1A) binding in vivo using both [¹¹C]CUMI-101 (agonist) and [¹¹C]WAY100635 (antagonist) in nonhuman primates. PET studies show that both tracers bind to known 5-HT(1A) receptor (5-HT(1A)R)-rich regions of baboon brain. The binding (BP(F)) of [¹¹C]CUMI-101 was lower on an average of 55% across the regions of interest (ROIs) compared to [¹¹C]WAY100635. This ratio is consistent with the in vitro binding data of agonist and antagonist 5-HT(1A)R ligands previously reported.


Subject(s)
Brain/metabolism , Nerve Tissue Proteins/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/metabolism , Serotonin 5-HT1 Receptor Antagonists/metabolism , Animals , Brain Mapping , Carbon Radioisotopes , Humans , Kinetics , Ligands , Papio , Piperazines/metabolism , Positron-Emission Tomography , Pyridines/metabolism , Triazines/metabolism
9.
Bioorg Med Chem Lett ; 22(15): 5104-7, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22749281

ABSTRACT

Synthesis and in vitro evaluation of [(18)F](R)-N-(4-bromo-2-fluorophenyl)-7-((1-(2-fluoroethyl)piperidin-3-yl)methoxy)-6-methoxyquinazolin-4-amine ((R)-[(18)F]FEPAQ or [(18)F]1), a potential imaging agent for the VEGFR2, using phosphor image autoradiography are described. Synthesis of 2, the desfluoroethyl precursor for (R)-FEPAQ was achieved from t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3) in five steps and in 50% yield. [(18)F]1 was synthesized by reaction of sodium salt of compound 2 with [(18)F]fluoroethyl tosylate in DMSO. The yield of [(18)F]1 was 20% (EOS based on [(18)F]F(-)) with >99% radiochemical purity and specific activity of 1-2 Ci/µmol (n=10). The total synthesis time was 75 min. The radiotracer selectively labeled VEGFR2 in slide-mounted sections of human brain and higher binding was found in surgically removed human glioblastoma sections as demonstrated by in vitro phosphor imager studies. These findings suggest [(18)F]1 may be a promising radiotracer for imaging VEGFR2 in brain using PET.


Subject(s)
Ligands , Quinazolines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/chemistry , Brain/metabolism , Drug Evaluation, Preclinical , Fluorine Radioisotopes/chemistry , Glioma/diagnosis , Glioma/metabolism , Glioma/pathology , Humans , Positron-Emission Tomography , Quinazolines/chemistry , Radiopharmaceuticals/chemistry , Stereoisomerism , Vascular Endothelial Growth Factor Receptor-2/metabolism
10.
Bioorg Med Chem Lett ; 22(6): 2172-4, 2012 Mar 15.
Article in English | MEDLINE | ID: mdl-22364813

ABSTRACT

Radiosynthesis of [N-methyl-(11)C](S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide ([(11)C]BBAC or [(11)C]3) and [N-methyl-(11)C] (S)-N-([1,1'-biphenyl]-2-yl)-1-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)propanoyl)pyrrolidine-2-carboxamide ([(11)C]BBPC or [(11)C]-4), two potential PET tracers for orexin2 receptors are described. Syntheses of non-radioactive standards 3, 4 and corresponding desmethyl precursors 1, 2 were achieved from common intermediate (S)-2-([1,1'-biphenyl]-2-yl)-1-(pyrrolidin-2-yl)ethanone. Methylation using [(11)C]CH(3)OTf in the presence of base in acetone afforded [(11)C]3 and [(11)C]4 in 30±5% yield (EOS) with >99 % radiochemical purities with a specific activity ranged from 2.5±0.5 Ci/µmol (EOB). The logP of [(11)C]3 and [(11)C]4 were determined as 3.4 and 2.8, respectively. The total synthesis time was 30 min from EOB. However, PET scans performed in a rhesus monkey did not show tracer retention or appropriate brain uptake. Hence [(11)C]3 and [(11)C]4 cannot be used as PET tracers for imaging orexin2 receptors.


Subject(s)
Amides/chemical synthesis , Pyrrolidines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Amides/metabolism , Amides/pharmacokinetics , Animals , Brain/diagnostic imaging , Brain/metabolism , Carbon Radioisotopes , Isotope Labeling , Macaca mulatta , Orexin Receptors , Positron-Emission Tomography , Pyrrolidines/metabolism , Pyrrolidines/pharmacokinetics , Radiopharmaceuticals/metabolism , Radiopharmaceuticals/pharmacokinetics , Stereoisomerism , Tissue Distribution
11.
Int J Toxicol ; 30(6): 611-8, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21994241

ABSTRACT

Sprague Dawley rats (10/sex/group) were given a single intravenous (iv) dose of CUMI-101 to determine acute toxicity of CUMI-101 and radiation dosimetry estimations were conducted in baboons with [(11)C]CUMI-101. Intravenous administration of CUMI-101 did not produce overt biologically or toxicologically significant adverse effects except transient hypoactivity immediately after dose in the mid- and high-dose groups, which is not considered to be a dose-limiting toxic effect. No adverse effects were observed in the low-dose group. The no observed adverse effect level (NOAEL) is considered to be 44.05 µg/kg for a single iv dose administration in rats. The maximum tolerated dose (MTD) was estimated to be 881 µg/kg for a single iv dose administration. The Medical Internal Radiation Dose (MIRDOSE) estimates indicate the maximum permissible single-study dosage of [(11)C]CUMI-101 in humans is 52 mCi with testes and urinary bladder as the critical organ for males and females, respectively.


Subject(s)
Piperazines/pharmacokinetics , Serotonin 5-HT1 Receptor Agonists/pharmacokinetics , Triazines/pharmacokinetics , Animals , Carbon Radioisotopes , Female , Ligands , Male , Papio , Piperazines/toxicity , Positron-Emission Tomography , Radiometry , Rats , Rats, Sprague-Dawley , Serotonin 5-HT1 Receptor Agonists/toxicity , Tissue Distribution , Triazines/toxicity
12.
Bioorg Med Chem ; 19(17): 5255-9, 2011 Sep 01.
Article in English | MEDLINE | ID: mdl-21821420

ABSTRACT

The serotonin receptor 6 (5-HT(6)) is implicated in the pathophysiology of cognitive diseases, schizophrenia, anxiety and obesity and in vivo studies of this receptor would be of value for studying the pathophysiology of these disorders. Therefore, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB399885), a selective and high affinity (pK(i)=9.11) 5-HT(6) antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue with [(11)C]MeOTf in order to determine the suitability of [(11)C]SB399885 to quantify 5-HT(6)R in living brain using PET. Desmethyl-SB399885 was prepared, starting from 1-(2-methoxyphenyl) piperazine hydrochloride, in excellent yield. The yield obtained for radiolabeling of [(11)C]SB399885 was 30±5% (EOS) and the total synthesis time was 30min at EOB. PET studies with [(11)C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [(11)C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [(11)C]SB399885 compared to known 5-HT(6)R distribution limits its usefulness for the in vivo quantification of 5-HT(6)R with PET.


Subject(s)
Piperazines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/chemical synthesis , Animals , Brain/diagnostic imaging , Carbon Radioisotopes/chemistry , Isotope Labeling , Papio , Piperazines/chemistry , Piperazines/pharmacokinetics , Positron-Emission Tomography , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Sulfonamides/pharmacokinetics , Tissue Distribution , Benzenesulfonamides
13.
J Cereb Blood Flow Metab ; 31(1): 243-9, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20571518

ABSTRACT

Positron emission tomography studies of 5-hydroxytryptamine (5-HT)(1A) receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT(1A) agonist radiotracer [(11)C]CUMI-101. This study evaluates the sensitivity of [(11)C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [(11)C]CUMI-101 intravenous bolus of 4.5 ± 1.5 mCi. Binding potential (BP(F)=B(avail)/K(D)) was measured before (n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BP(F) (P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [(11)C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BP(F) may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.


Subject(s)
Piperazines/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin/metabolism , Triazines/pharmacokinetics , Animals , Binding, Competitive/drug effects , Citalopram/administration & dosage , Citalopram/pharmacology , Fenfluramine/administration & dosage , Fenfluramine/pharmacology , Image Processing, Computer-Assisted , Injections, Intravenous , Male , Papio anubis , Positron-Emission Tomography , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/pharmacology , Synapses/drug effects , Synapses/metabolism
14.
J Nucl Med ; 51(12): 1892-900, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21098796

ABSTRACT

UNLABELLED: The serotonin (5-hydroxytryptamine, or 5-HT) type 1A receptor (5-HT(1A)R) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-(11)C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione ((11)C-CUMI-101), a novel 5-HT(1A) agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of (11)C-CUMI-101 for human PET studies. METHODS: PET scans were obtained for 7 adult human volunteers. (11)C-CUMI-101 was injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 10 different models using metabolite-corrected arterial input functions or reference region approaches and several outcome measures. RESULTS: When using binding potential (BP(F) = B(avail)/K(D) [total available receptor concentration divided by the equilibrium dissociation constant]) as the outcome measure, the likelihood estimation in the graphical analysis (LEGA) model performed slightly better than the other methods evaluated at full scan duration. The average test-retest percentage difference was 9.90% ± 5.60%. When using BP(ND) (BP(ND) = f(nd) × B(avail)/K(D); BP(ND) equals the product of BP(F) and f(nd) [free fraction in the nondisplaceable compartment]), the simplified reference tissue method (SRTM) achieved the lowest percentage difference and smallest bias when compared with nondisplaceable binding potential obtained from LEGA using the metabolite-corrected plasma input function (r(2) = 0.99; slope = 0.92). The time-stability analysis indicates that a 120-min scan is sufficient for the stable estimation of outcome measures. Voxel results were comparable to region-of-interest-based analysis, with higher spatial resolution. CONCLUSION: On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood-brain barrier permeability, and plasma and brain kinetics, (11)C-CUMI-101 is suitable for the imaging of high-affinity 5-HT(1A) binding in humans.


Subject(s)
Piperazines , Radiopharmaceuticals , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists , Triazines , Adult , Blood-Brain Barrier/diagnostic imaging , Brain/diagnostic imaging , Brain/metabolism , Female , Humans , Image Interpretation, Computer-Assisted , Kinetics , Magnetic Resonance Imaging , Male , Models, Statistical , Piperazines/pharmacokinetics , Positron-Emission Tomography , Radiopharmaceuticals/pharmacokinetics , Reproducibility of Results , Serotonin Receptor Agonists/pharmacokinetics , Triazines/pharmacokinetics
15.
Bioorg Med Chem Lett ; 20(12): 3654-7, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20529687

ABSTRACT

Radiosynthesis and in vivo evaluation of [N-methyl-(11)C] 5-methyl-3-[4-(3-phenylallyl)-piperazin-1-ylmethyl]-3,3a,4,5-tetrahydroisoxazolo[4,3-c]quinoline (1), a potential PET tracer for alpha2-adrenergic receptors is described. Syntheses of nonradioactive standard 1 and corresponding desmethyl precursor 2 were achieved from 2-aminobenzaldehyde in 40% and 65% yields, respectively. Methylation using [(11)C]CH(3)I in presence of aqueous potassium hydroxide in DMSO afforded [(11)C]1 in 25% yield (EOS) with >99% chemical and radiochemical purities with a specific activity ranged from 3-4 Ci/micromol (n=6). The total synthesis time was 30 min from EOB. PET studies in anesthetized baboon show that [(11)C]1 penetrates BBB and accumulates in alpha2A-AR enriched brain areas.


Subject(s)
Isoxazoles , Quinolines , Radiopharmaceuticals/chemical synthesis , Receptors, Adrenergic, alpha-2/analysis , Animals , Benzaldehydes/chemistry , Blood-Brain Barrier/metabolism , Brain/metabolism , Carbon Radioisotopes , Isotope Labeling , Isoxazoles/chemical synthesis , Methylation , Papio , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution
16.
Bioorg Med Chem Lett ; 20(12): 3499-501, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20494576

ABSTRACT

Synthesis, in vitro and in vivo evaluation of [O-methyl-(11)C]dimethylamino-3(4-methoxyphenyl)-3H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-one (1), a potential imaging agent for mGluR1 receptors using PET are described. Synthesis of the corresponding desmethyl precursor 2 was achieved by demethylation of the methoxyphenyl compound 1 in 90% yield. Methylation using [(11)C]MeOTf in presence of NaOH afforded [(11)C]1 in 30% yield (EOS) with >99% chemical and radiochemical purities and with a specific activity of 3-5Ci/micromol (n=6). The total synthesis time was 30min from EOB. The radiotracer selectively labeled mGluR1 receptors in slide-mounted sections of postmortem human brain containing cerebellum, hippocampus, prefrontal cortex and striatum as demonstrated by in vitro autoradiography using phosphor-imaging. PET studies in anesthetized baboon show that [(11)C]1 penetrates the BBB and accumulates in cerebellum, a region reported to have higher expression of mGluR1. These findings suggest [(11)C]1 is a promising PET radiotracer candidate for mGluR1.


Subject(s)
Positron-Emission Tomography/methods , Pyrimidinones , Radiopharmaceuticals/chemical synthesis , Receptors, Metabotropic Glutamate/analysis , Animals , Blood-Brain Barrier/metabolism , Brain Chemistry , Carbon Radioisotopes , Cerebellum/chemistry , Humans , Isotope Labeling , Ligands , Papio , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics
17.
J Nucl Med ; 49(4): 587-96, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18344443

ABSTRACT

UNLABELLED: Several lines of evidence demonstrate involvement of serotonin 1A receptors (5-HT1ARs) in the pathophysiology of neuropsychiatric disorders such as depression, suicidal behavior, schizophrenia, and Alzheimer's disease. We recently published the synthesis and initial evaluation of [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (11C-MMP), a 5-HT1AR agonist. Here we determine the optimal modeling parameters for 11C-MMP under its new name, 11C-CUMI-101, in Papio anubis. METHODS: PET scans were performed on 2 adult male P. anubis; 166.5 MBq +/- 43.0 (4.50 +/- 1.16 mCi) of 11C-CUMI-101 were injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 4 different models (1- and 2-tissue compartment iterative and noniterative kinetic models, basis pursuit, and likelihood estimation in graphical analysis [LEGA]), using binding potential (BPF = Bmax/Kd) (Bmax = maximum number of binding sites; Kd = dissociation constant) as the outcome measure. Arterial blood sampling and metabolite-corrected arterial input function were used for full quantification of BPF. To assess the performance of each model, we compared results using 6 different metrics (percentage difference, within-subject mean sum of squares [WSMSS] for reproducibility; variance across subjects, intraclass correlation coefficient [ICC] for reliability; identifiability based on bootstrap resampling of residuals; and time stability analysis to determine minimal required scanning time) at each of 6 different scanning durations. Models were also evaluated on scans acquired after injecting the 5-HT1A antagonist [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] [WAY100635] 0.5 mg/kg, intravenous) and the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin) [8-OH-DPAT] 2 mg/kg, intravenous). RESULTS: All metabolites are more polar than 11C-CUMI-101, and no significant change in metabolites was observed in the blocking studies. The free fraction is 59% +/- 3%. We determined that 100 min of scanning time is adequate and that for the region-of-interest (ROI)-level analysis, the LEGA model gives the best results. The median test-retest percentage difference for BPF is 11.15% +/- 4.82% across all regions, WSMSS = 2.66, variance = 6.07, ICC = 0.43, and bootstrap identifiability = 0.59. Preadministration of WAY100635 and 8-OH-DPAT resulted in 87% and 76% average reductions in BPF values, respectively, across ROIs. CONCLUSION: On the basis of the measurable free fraction, high affinity and selectivity, adequate blood-brain permeability, and favorable plasma and brain kinetics, 11C-CUMI-101 is an excellent candidate for imaging high-affinity 5-HT1ARs in humans.


Subject(s)
Carbon Radioisotopes , Piperazines , Positron-Emission Tomography , Radiopharmaceuticals , Receptor, Serotonin, 5-HT1A/analysis , Serotonin Receptor Agonists , Triazines , 8-Hydroxy-2-(di-n-propylamino)tetralin/metabolism , Animals , Male , Models, Biological , Papio , Piperazines/metabolism , Pyridines/metabolism , Serotonin 5-HT1 Receptor Agonists
18.
Eur J Nucl Med Mol Imaging ; 34(7): 1050-60, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17221184

ABSTRACT

PURPOSE: Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons. METHODS: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT. RESULTS: MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 +/- 5% (n = 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT. CONCLUSION: We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Piperazines/pharmacokinetics , Positron-Emission Tomography/methods , Serotonin 5-HT1 Receptor Agonists , Triazines/pharmacokinetics , Animals , Drug Evaluation, Preclinical , Humans , Isotope Labeling/methods , Papio , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution
19.
Bioorg Med Chem ; 15(4): 1802-7, 2007 Feb 15.
Article in English | MEDLINE | ID: mdl-17166726

ABSTRACT

Synthesis of [18F]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ([18F]celecoxib), a selective COX-2 inhibitor, is achieved via a bromide to [18F]F- exchange reaction. Synthesis of the precursor for radiolabeling was achieved from 4'-methylacetophenone in four steps with 22% overall yield. Under non-radioactive conditions, fluorination was achieved using TBAF in DMSO at 135 degrees C in 80% yield. Synthesis of [18F]celecoxib was achieved using [18F]TBAF in DMSO at 135 degrees C in 10+/-2% yield (EOS) with >99% chemical and radiochemical purities. The specific activity was 120+/-40 mCi/micromol (EOB). [18F]celecoxib was found to be stable in ethanol, however, de[18F]fluorination (6.5%) was observed after 4 h in 10% ethanol-saline solution. Rodent PET studies show bone labeling indicating in vivo de[18F]fluorination of [18F]celecoxib. PET studies in baboon indicated a lower rate of de[18F]fluorination than rat and retention of radioactivity in brain regions consistent with the known distribution of COX-2. A radiolabeling method that can generate consistent high specific activity is needed for routine human use.


Subject(s)
Cyclooxygenase 2/analysis , Membrane Proteins/analysis , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Bone and Bones/diagnostic imaging , Brain/diagnostic imaging , Cyclooxygenase 2/pharmacokinetics , Drug Stability , Fluorine Radioisotopes , Humans , Membrane Proteins/pharmacokinetics , Papio , Radiopharmaceuticals/pharmacokinetics , Rodentia , Sulfonamides/pharmacokinetics , Tissue Distribution , Benzenesulfonamides
20.
Eur J Nucl Med Mol Imaging ; 34(5): 688-693, 2007 May.
Article in English | MEDLINE | ID: mdl-17180600

ABSTRACT

PURPOSE: Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter's role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates. METHODS: Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test-retest and blocking conditions using 1 mg/kg nisoxetine. RESULTS: MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine. CONCLUSION: Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [(11)C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.


Subject(s)
Adrenergic Uptake Inhibitors , Carbon Radioisotopes , Diagnostic Imaging/instrumentation , Morpholines , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Positron-Emission Tomography/methods , Animals , Diagnostic Imaging/methods , Fluoxetine/analogs & derivatives , Image Processing, Computer-Assisted , Kinetics , Ligands , Papio , Reboxetine , Sensitivity and Specificity , Serotonin Plasma Membrane Transport Proteins/metabolism , Time Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...